This research is directed at developing non-viral gene medicines to treat pulmonary diseases such as emphysema, cystic fibrosis, asthma, infections or COPD that may require gene expression in lower airways and alveolar spaces. Previous studies have demonstrated that cationic lipid formulations of DNA plasmids provide effective uptake of genes into epithelial cells of the upper airways after direct instillation. A clinical trial using direct instillation to express alpha 1- antitrypsin (AAT) in AAT deficient patients is currently underway. The present work is aimed at developing formulations for inhalation that provide reproducible bioavailability of the DNA plasmid and gene expression in the lower airways and alveolus. AAT is a leading candidate gene for pulmonary gene therapy and may be indicated for various acute or chronic pulmonary inflammatory disorders as well as for genetic emphysema (AAT deficiency). The hypothesis is that expression of AAT at sufficient levels within the lower airways and alveoli will protect the lung from protease injury. This Phase I application focuses on development of delivery systems suitable for clinical use. Phase II will focus on demonstrating the pharmacological effect of gene expression in animal models of disease.